This application relates to the following U.S. patent applications:
Each of these U.S. patents and applications also is entirely incorporated herein by reference.
Treatment of HIV-infected individuals is one of the most pressing biomedical problems of recent times. A promising new therapy has emerged as an important method for preventing or inhibiting the rapid proliferation of the virus in human tissue. HIV-protease inhibitors block a key enzymatic pathway in the virus resulting in substantially decreased viral loads, which slows the steady decay of the immune system and its resulting deleterious effects on human health. The HIV-protease inhibitor nelfinavir mesylate of formula 7 
has been shown to be an effective treatment for HIV-infected individuals. Nelfinavir mesylate is disclosed in U.S. Pat. No. 5,484,926, issued Jan. 16, 1996. This patent is entirely incorporated by reference into this patent application.
The present inventors have discovered useful intermediate compounds that can be used in several reaction schemes to make nelfinavir mesylate. The present inventors also have discovered new methods for making nelfinavir mesylate from the free base nelfinavir of formula 4: 
The nelfinavir free base also is disclosed in U.S. Pat. No. 5,484,926.
It is an object of this invention to provide compounds and intermediates useful for making HIV-protease inhibitors and methods of making HIV-protease inhibitors. Such inhibitors are useful for treating HIV-infected individuals.
In a first aspect, the invention relates to compounds of formula 3: 
wherein R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8 
xe2x80x83wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9 
xe2x80x83wherein each R3 is independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10 
xe2x80x83wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen, with the proviso that when R1 is xe2x80x94CH3, X cannot be xe2x80x94OCH3 or xe2x80x94OH, and when R1 is CH3C(O)xe2x80x94, X cannot be xe2x80x94OH;
or a pharmaceutically acceptable salt or solvate thereof.
In various preferred embodiments of the invention, R1 is xe2x80x94C(O)CH3 and/or X is a halogen, preferably, Cl.
In another aspect, the invention relates to compounds of formula 2: 
xe2x80x83wherein R1 is a C2 to C8 alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, or a group of formula 8 
xe2x80x83wherein R2 is a C2 to C8 alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9 
xe2x80x83wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10 
xe2x80x83wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or a pharmaceutically acceptable salt or solvate thereof.
This invention further relates to methods for making the compounds of formulae 2 and 3. In a method for making a compound of formula 2: 
a compound according to formula 1, shown below, 
is reacted under suitable and sufficient conditions to add an R1 protecting group and form a compound of formula 2. In this instance,
R1 is a C2 to C8 alkyl group; a cycloalkyl group; a heterocycloalkyl group; an aryl group; a heteroaryl group; or a group of formula 8 
xe2x80x83wherein R2 is a C2 to C8 alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or R1 is a group of formula 9 
xe2x80x83wherein each R3 is independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or R1 is a group of formula 10 
xe2x80x83wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group.
This invention includes a method of making a compound according to formula 3 
This method includes adding, under suitable and sufficient conditions, a suitable protecting group R1 and a leaving group X to a compound of formula 1 
In this instance,
R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8 
xe2x80x83wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or R1 is a group of formula 9 
xe2x80x83wherein each R3 is independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10 
xe2x80x83wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen, with the proviso that when R1 is xe2x80x94CH3, X cannot be xe2x80x94OCH3 or xe2x80x94OH, and when R1 is CH3C(O)xe2x80x94, X cannot be xe2x80x94OH. As noted above, in certain embodiments, R1 is xe2x80x94C(O)CH3 and/or X is a halogen, preferably, Cl.
A compound according to formula 3, as defined above, also can be made from a compound of formula 2. The reaction proceeds by adding a suitable leaving group X to the compound of formula 2. In this instance, formula 2 is as defined below: 
wherein R1 is alkyl; cycloalkyl, heterocycloalkyl; aryl; heteroaryl; or a group of formula 8 
xe2x80x83wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9 
xe2x80x83wherein each R3 is independently an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10 
xe2x80x83wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group. Additionally, in this instance, X is defined as OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen. In this method, when R1 is xe2x80x94CH3, X cannot be xe2x80x94OCH3 or xe2x80x94OH, and when R1 is CH3C(O)xe2x80x94, X cannot be xe2x80x94OH.
This invention further relates to methods for making HIV-protease inhibitors. One HIV-protease inhibitor produced by a method according to this invention is a compound of formula 4, illustrated below: 
In this method, a compound of formula 3 
wherein R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8 
xe2x80x83wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9 
xe2x80x83wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10 
xe2x80x83wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen,
is reacted under suitable and sufficient conditions to form the compound of formula 4. Again, for one preferred embodiment of this process, the variable R1 represents xe2x80x94C(O)CH3 and/or the variable X represents Cl.
The compound according to formula 4, identified above, also can be prepared by deprotecting a compound of formula 5 
and reacting with it, under sufficient conditions, a compound of formula 3. In this instance, the compound according to formula 3 is 
wherein R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8 
xe2x80x83wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9 
xe2x80x83wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10 
xe2x80x83wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen.
In another embodiment of this invention, a compound of formula 4, as identified above, can be prepared by combining a compound of formula 3: 
wherein R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8 
xe2x80x83wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9 
xe2x80x83wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10 
xe2x80x83wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen,
with a compound of formula 6 
under conditions sufficient and suitable to obtain the compound of formula 4.
This invention further relates to methods of making a compound of formula 7. In one embodiment, the compound of formula 7 
is produced by converting a compound of formula 4 
under sufficient and suitable conditions to the compound of formula 7. In this method, the conversion of the compound of formula 4 to the compound of formula 7 takes place by:
(a) contacting the compound of formula 4 with an organic solvent;
(b) contacting the compound of formula 4 with methanesulfonic acid under conditions sufficient to form a compound of formula 7; and
(c) spray drying the compound of formula 7. In a more specific embodiment of this method, the organic solvent is ethanol.
In another method for making a compound of formula 7 from a compound of formula 4, the following procedure is followed:
(a) the compound of formula 4, a suitable solvent, and methanesulfonic acid are combined to form the compound of formula 7, the compound of formula 7 being dissolved in solution;
(b) a first antisolvent is added to the solution containing the compound of formula 7;
(c) the compound of formula 7 and the first antisolvent are agitated together to form a product having a solid phase and a liquid phase; and
(d) the product is filtered and washed with a second antisolvent, the second antisolvent being the same as or different from the first antisolvent, to obtain a solid final product according to formula 7. After the solid final product is washed, it can be dried by any appropriate method or means. Tetrahydrofuran can be used as the solvent, and diethylether can be used as at least one antisolvent, preferably at least the first antisolvent.
This invention also relates to a method of making a compound according to formula 4 (as defined above) from a compound according to formula 2. In this method, a compound according to formula 2 is reacted under sufficient and suitable conditions to form the compound of formula 4. In this instance, the compound of formula 2 is defined as follows: 
wherein R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; a group of formula 8 
xe2x80x83wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9 
xe2x80x83wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10 
xe2x80x83wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group.
Yet another embodiment of this invention relates to a method of making a compound of formula 7, defined above. In this method, a compound according to formula 5 
is deprotected. Then, the deprotected compound of formula 5 is reacted, under sufficient and suitable conditions, with a compound of formula 3. Formula 3, in this instance, is defined as follows: 
wherein R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; or a group of formula 8 
xe2x80x83wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, or Oxe2x80x94R6, wherein R6 is an alkyl group, an aralkyl group, or an aryl group;
or further wherein R1 is a group of formula 9 
xe2x80x83wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group;
or further wherein R1 is a group of formula 10 
xe2x80x83wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7, wherein R7 is alkyl or aryl; halogen; pseudohalogen; OSO2R8, wherein R8 is alkyl or aryl; heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic bonded through the oxygen. The reaction of compounds 3 and 5 produces a compound of formula 4, described above. The compound according to formula 4 is then converted to the compound of formula 7, for example, by one of the methods described above.
This invention relates to compounds and intermediates useful for making HIV-protease inhibitors, methods of making the compounds and intermediates, and methods of making HIV-protease inhibitors.
As mentioned above, one aspect of this invention relates to compounds that are useful (e.g., as starting materials or intermediates) for making HIV-protease inhibitors. One such group of compounds are identified in this application by formula 3, shown below: 
wherein R1 is alkyl; cycloalkyl; heterocycloalkyl; aryl; heteroaryl; a group of formula 8 
xe2x80x83wherein R2 is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, Oxe2x80x94R6 (wherein R6 is an alkyl group, an aralkyl group, or an aryl group); a group of formula 9 
xe2x80x83wherein R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; or a group of formula 10 
xe2x80x83wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and
X is OH; OR7 (wherein R7 is alkyl or aryl); halogen; pseudohalogen, including azide, cyanide, isocyanate and isothiocyanate; OSO2R8 (wherein R8 is alkyl or aryl); heteroaryl bonded through the heteroatom; or N-hydroxyheterocyclic, including hydroxysuccinimide or hydroxybenzotriazole ester, bonded through the oxygen, with the proviso that when R1 is xe2x80x94CH3, X cannot be xe2x80x94OCH3 or xe2x80x94OH, and when R1 is CH3C(O)xe2x80x94, X cannot be xe2x80x94OH; and to pharmaceutically acceptable salts and solvates thereof. Preferably X is a halogen, particularly, Cl.
The present invention also is directed to novel compounds of formula 2 
wherein R1 is a C2 to C8 alkyl group; a cycloalkyl group; a heterocycloalkyl group; an aryl group; a heteroaryl group; a group of formula 8 
wherein R2 is a C2 to C8 alkyl group, a cycloalkyl group, a heterocycloalkyl group, Oxe2x80x94R6 (wherein R6 is an alkyl group, an aralkyl group, or an aryl group); a group of formula 9 
wherein each R3 independently is an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; or a group of formula 10 
wherein R4 and each R5 independently are an alkyl group, a cycloalkyl group, a heterocycloalkyl group, an aryl group, or a heteroaryl group; and to pharmaceutically acceptable salts and solvates thereof.
When R1 is a group of formula 8 where R2 is alkyl, R1 can be, for example, acetate, propanoate, butanoate, pivaloate, or any related alkyl ester or mixed carbonate with a group such as benzyl . Other examples of R1 groups where R1 is a group of formula 8 include esters of aromatic and heteroaromatic acids, such as benzoate, substituted benzoate, 1- or 2-naphthoate or substituted 1- or 2-naphthoate, or a substituted 5- or 6-membered heteroaromatic ester. Examples of R1 groups where R1 is an alkyl include methyl, substituted methyl, ethyl, propyl, and butyl. Examples of R1 when R1 is a silyl ether of formula 9 include trimethylsilyl, t-butyldimethylsilyl, triisopropylsilyl, triphenylsilyl, and silyl ethers where the alkyl groups R3 are some combination of simple alkyl and aryl groups. Examples of R1 where R1 is part of an acetal or ketal of formula 10 include acetonide, cyclohexylidene ketal, benzylidene acetal, 2-methoxyethoxyethyl acetal, and related acetals and ketals where R4 and R5 are alkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl. In certain preferred compounds of formulae 2 and 3, and in pharmaceutically acceptable salts and solvates thereof, R1 is xe2x80x94C(O)CH3; alternatively expressed, R2 in a group of formula 8 is CH3.
The present invention is further directed to various methods of making compounds of formulae 2, 3, 4 (nelfinavir free base), and 7 (nelfinavir mesylate), as described above. Other methods of preparing nelfinavir free base using compounds of formulae 2 and 3 are described in U.S. patent application Ser. No. 08/708,607, filed Sep. 5, 1996, which application also is entirely incorporated herein by reference. Other methods of using compounds of Formulae 2 and 3 are disclosed in JP 95-248183 and JP 95-248184, each of which is entirely incorporated herein by reference.
As used in the present application, the following definitions apply:
The term xe2x80x9calkylxe2x80x9d as used herein refers to substituted or unsubstituted, straight or branched chain groups, preferably, having one to eight, more preferably having one to six, and most preferably having from one to four carbon atoms. The term xe2x80x9cC1-C6 alkylxe2x80x9d represents a straight or branched alkyl chain having from one to six carbon atoms. Exemplary C1-C6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, neo-pentyl, hexyl, isohexyl, and the like. The term xe2x80x9cC1-C6 alkylxe2x80x9d includes within its definition the term xe2x80x9cC1-C4 alkyl.xe2x80x9d
The term xe2x80x9ccycloalkylxe2x80x9d represents a substituted or unsubstituted, saturated or partially saturated, mono- or poly-carbocyclic ring, preferably having 5-14 ring carbon atoms. Exemplary cycloalkyls include monocyclic rings having from 3-7, preferably 3-6, carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like. Exemplary cycloalkyls are C5-C7 cycloalkyls, which are saturated hydrocarbon ring structures containing from five to seven carbon atoms.
The term xe2x80x9carylxe2x80x9d as used herein refers to an aromatic, monovalent monocyclic, bicyclic, or tricyclic radical containing 6, 10, 14, or 18 carbon ring atoms, which may be unsubstituted or substituted, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted by one or more suitable substituents. Illustrative examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, fluoren-2-yl, indan-5-yl, and the like.
The term xe2x80x9chalogenxe2x80x9d represents chlorine, fluorine, bromine, or iodine. The term xe2x80x9chaloxe2x80x9d represents chloro, fluoro, bromo, or iodo.
The term xe2x80x9ccarbocyclexe2x80x9d represents a substituted or unsubstituted aromatic or a saturated or a partially saturated 5-14 membered monocyclic or polycyclic ring, which is substituted or unsubstituted, such as a 5- to 7-membered monocyclic or 7- to 10-membered bicyclic ring, wherein all the ring members are carbon atoms.
A xe2x80x9cheterocycloalkyl groupxe2x80x9d is intended to mean a non-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical, which is saturated or unsaturated, containing 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, add which includes 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen, and sulfur, wherein the radical is unsubstituted or substituted, and to which may be fused one or more cycloalkyl groups, aryl groups, or heteroaryl groups, which themselves may be unsubstituted or substituted. Illustrative examples of heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidyl, piperidyl, piperazinyl, morpholinyl, tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl, dihydrofuryl, tetrahydropyranyl, dihydropyranyl, 1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl, 1,3-oxathianyl, 1,3-dithianyl, azabicylo[3.2.1]octyl, azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl, 1,5,9-triazacyclododecyl, and the like.
A xe2x80x9cheteroaryl groupxe2x80x9d is intended to mean an aromatic monovalent monocyclic, bicyclic, or tricyclic radical containing 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 ring atoms, including 1, 2, 3, 4, or 5 heteroatoms selected from nitrogen, oxygen, and sulfur, which may be unsubstituted or substituted, and to which may be fused one or more cycloalkyl groups, heterocycloalkyl groups, or aryl groups, which themselves may be unsubstituted or substituted. Illustrative examples of heteroaryl groups include, but are not limited to, thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzo[b]thienyl, naphtho[2,3-b]thianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxyalinyl, quinzolinyl, benzothiazolyl, benzimidazolyl, tetrahydroquinolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, and phenoxazinyl.
The term xe2x80x9cacylxe2x80x9d represents L6C(O)L4, wherein L6 is a single bond, xe2x80x94O, or xe2x80x94N, and further wherein L4 is preferably alkyl, amino, hydroxyl, alkoxyl, or hydrogen. The alkyl, amino, and alkoxyl groups optionally can be substituted. An exemplary acyl is a C1-C4 alkoxycarbonyl, which is a straight or branched alkoxyl chain having from one to four carbon atoms attached to a carbonyl moiety. Exemplary C1-C4 alkoxycarbonyl groups include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, and the like. Another exemplary acyl is a carboxy wherein L6 is a single bond and L4 is alkoxyl, hydrogen, or hydroxyl. A further exemplary acyl is N-(C1-C4)alkylcarbamoyl (L6 is a single bond and L4 is an amino), which is a straight or branched alkyl chain having from one to four carbon atoms attached to the nitrogen atom of a carbamoyl moiety. Exemplary N-(C1-C4)alkylcarbamoyl groups include N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N-isopropylcarbamoyl, N-butylcarbamoyl, and N-t-butylcarbamoyl, and the like. Yet another exemplary acyl is N,N-di(C1-C4)alkylcarbamoyl, which has two straight or branched alkyl chains, each having from one to four carbon atoms attached to the nitrogen atom of a carbamoyl moiety. Exemplary N,N-di(C1-C4)alkylcarbamoyl groups include N,N-dimethylcarbamoyl, N,N-ethylmethylcarbamoyl, N,N-methylpropylcarbamoyl, N,N-ethylisopropylcarbamoyl, N,N-butylmethylcarbamoyl, N,N-sec-butylethylcarbamoyl, and the like.
Suitable protecting groups are recognizable to those skilled in the art. Examples of suitable protecting groups can be found in T. Green and P. Wuts, Protective Groups in Organic Synthesis (2d ed. 1991), which is incorporated herein by reference.
The term xe2x80x9caralkylxe2x80x9d as used herein refers to any substituted or unsubstituted group that is sp3 hybridized at the point of attachment that also possesses an aromatic ring or rings with that group.
The term xe2x80x9cpseudohalogenxe2x80x9d as used herein refers to azides, cyanides, isocyanates, and isothiocyanates.
The term xe2x80x9cN-hydroxyheterocyclicxe2x80x9d as used herein refers to substituted and unsubstituted groups having an oxygen atom at the point of attachment that is also bonded to the nitrogen of a nitrogen heterocyclic ring or ring system. Examples of such groups include: 
The term xe2x80x9calkyl esterxe2x80x9d as used herein refers to ester groups where the group attached to the esterifying oxygen is an alkyl group.
The term xe2x80x9cmixed carbonatexe2x80x9d as used herein refers to compounds containing the functional group 
where Ra and Rb independently are alkyl, aryl, or aralkyl groups.
The term xe2x80x9cester of an aromatic or heteroaromatic acidxe2x80x9d as used herein refers to carboxylic acids wherein the carboxyl group is attached directly to a substituted or unsubstituted aromatic or heteroaromatic ring, such as benzoic acid or 2-furoic acid.
The term xe2x80x9cDABCOxe2x80x9d as used herein refers to the reagent 1,4-diazabicyclo[2.2.2]octane.
The term xe2x80x9cDBNxe2x80x9d as used herein refers to the reagent 1,5-diazabicyclo[4.3.0]non-5-ene.
The term xe2x80x9cDBUxe2x80x9d as used herein refers to the reagent 1,8-diazabicyclo[5.4.0]undec-7-ene.
The term xe2x80x9csilyl etherxe2x80x9d as used herein refers to the group: 
wherein Rc, Rd, and Re independently are alkyl, aryl or aralkyl groups.
The term xe2x80x9cperfluoralkanesulfonatexe2x80x9d as used herein refers to alkane sulfonate esters wherein one or more of the hydrogens are replaced by fluorines.
The term xe2x80x9cvinyl alkyl etherxe2x80x9d as used herein refers to ether groups where an alkyl group and a substituted or unsubstituted olefin-containing group are bonded to the ethereal oxygen, and the olefin-containing group is bonded to the ethereal oxygen at one of the doubly-bonded carbons.
The term xe2x80x9carylsufonic acidxe2x80x9d as used herein refers to groups of formula: 
wherein Ar is a substituted or unsubstituted aromatic ring.
The term xe2x80x9cleaving groupxe2x80x9d as used herein refers to any group that departs from a molecule in a substitution reaction by breakage of a bond. Examples of leaving groups include, but are not limited to, halides, arenesulfonates, alkylsulfonates, and triflates.
The term xe2x80x9carenesulfonatexe2x80x9d as used herein refers to any substituted or unsubstituted group that is an ester of an arylsulfonic acid.
The term xe2x80x9calkyl or aryl carbodiimidesxe2x80x9d as used herein refers to any reagent of formula Rfxe2x80x94Nxe2x95x90Cxe2x95x90Nxe2x80x94Rg wherein Rf and Rg independently are aryl, alkyl, or aralkyl.
The term xe2x80x9cDMFxe2x80x9d as used herein refers to the solvent N,N-dimethylformamide.
The term xe2x80x9cNMPxe2x80x9d as used herein refers to the solvent N-methyl-2-pyrolidinone.
The term xe2x80x9cTHFxe2x80x9d as used herein refers to the solvent tetrahydrofuran.
The term xe2x80x9calkyl thiolatesxe2x80x9d as used herein refers to substituted or unsubstituted compounds that are metal salts of alkanethiols.
The term xe2x80x9ctrialkylsilyl halidesxe2x80x9d as used herein refers to compounds having a silicon that holds 3 alkyl groups that may be the same or different.
The term xe2x80x9chydrogenolysisxe2x80x9d as used herein refers to a reaction in which a single bond is broken and hydrogens become bonded to the atoms that were formerly bonded.
Examples of substituents for alkyl and aryl include mercapto, thioether, nitro (NO2), amino, aryloxyl, halogen, hydroxyl, alkoxyl, and acyl, as well as aryl, cycloalkyl, and saturated and partially saturated heterocycles. Examples of substituents for cycloalkyl include those listed above for alkyl and aryl, as well as aryl and alkyl.
Exemplary substituted aryls include a phenyl or naphthyl ring substituted with one or more substituents, preferably one to three substituents, independently selected from halo; hydroxy; morpholino(C1-C4)alkoxy carbonyl; pyridyl (C1-C4)alkoxycarbonyl; halo (C1-C4)alkyl; C1-C4 alkyl; C1-C4 alkoxy; carboxy; C1-C4 alkoxycarbonyl; carbamoyl; N-(C1-C4)alkylcarbamoyl; amino; C1-C4alkylamino; di(C1-C4)alkylamino; or a group of the formula xe2x80x94(CH2)axe2x80x94R7 where a is 1, 2, 3, or 4, and R7 is hydroxy, C1-C4 alkoxy, carboxy, C1-C4 alkoxycarbonyl, amino, carbamoyl, C1-C4 alkylamino, or di(C1-C4)alkylamino.
Another substituted alkyl is halo(C1-C4)alkyl, which represents a straight or branched alkyl chain having from one to four carbon atoms with 1-3 halogen atoms attached to it. Exemplary halo(C1-C4)alkyl groups include chloromethyl, 2-bromoethyl, 1-chloroisopropyl, 3-fluoropropyl, 2,3-dibromobutyl, 3-chloroisobutyl, iodo-t-butyl, trifluoromethyl, and the like.
Another substituted alkyl is hydroxy(C1-C4)alkyl, which represents a straight or branched alkyl chain having from one to four carbon atoms with a hydroxy group attached to it. Exemplary hydroxy(C1-C4)alkyl groups include hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxyisopropyl, 4-hydroxybutyl, and the like.
Yet another substituted alkyl is C1-C4 alkylthio(C1-C4)alkyl, which is a straight or branched C1-C4 alkyl group with a C1-C4 alkylthio group attached to it. Exemplary C1-C4 alkylthio(C1-C4)alkyl groups include methylthiomethyl, ethylthiomethyl, propylthiopropyl, sec-butylthiomethyl, and the like.
Yet another exemplary substituted alkyl is heterocycle(C1-C4)alkyl, which is a straight or branched alkyl chain having from one to four carbon atoms with a heterocycle attached to it. Exemplary heterocycle(C1-C4)alkyls include pyrrolylmethyl, quinolinylmethyl, 1-indolylethyl, 2-furylethyl, 3-thien-2-ylpropyl, 1-imidazolylisopropyl, 4-thiazolylbutyl, and the like.
Yet another substituted alkyl is aryl(C1-C4)alkyl, which is a straight or branched alkyl chain having from one to four carbon atoms with an aryl group attached to it. Exemplary aryl(C1-C4)alkyl groups include phenylmethyl, 2-phenylethyl, 3-naphthyl-propyl, 1-naphthylisopropyl, 4-phenylbutyl, and the like.
The heterocycloalkyls and heteroaryls can, for example, be substituted with 1, 2, or 3 substituents independently selected from halo; halo(C1-C4)alkyl; C1-C4 alkyl; C1-C4 alkoxy; carboxy; C1-C4 alkoxycarbonyl; carbamoyl; N-(C1-C4)alkylcarbamoyl; amino; C1-C4 alkylamino; di(C1-C4)alkylamino; or a group having the structure xe2x80x94(CH2)9xe2x80x94R7 where a is 1, 2, 3, or 4, and R7 is hydroxy, C1-C4 alkoxy, carboxy, C1-C4 alkoxycarbonyl, amino, carbamoyl, C1-C4alkylamino, or di(C1-C4)alkylamino.
Examples of substituted heterocycloalkyls include, but are not limited to, 3-N-t-butyl carboxamide decahydroisoquinolinyl and 6N-t-butyl carboxamide octahydro-thieno[3,2-c]pyridinyl. Examples of substituted heteroaryls include, but are not limited to, 3-methylimidazolyl, 3-methoxypyridyl, 4-chloroquinolinyl, 4-aminothiazolyl, 8-methylquinolinyl, 6-chloroquinoxalinyl, 3-ethylpyridyl, 6-methoxybenzimidazolyl, 4-hydroxyfuryl, 4-methylisoquinolinyl, 6,8-dibromoquinolinyl, 4,8-dimethylnaphthyl, 2-methyl-1,2,3,4-tetrahydroisoquinolinyl, N-methyl-quinolin-2-yl, 2-t-butoxycarbonyl1,2,3,4-isoquinolin-7-yl, and the like.
A xe2x80x9cpharmaceutically acceptable solvatexe2x80x9d is intended to mean a solvate that retains the biological effectiveness and properties of the biologically active components of compounds of formulae 2 and 3.
Examples of pharmaceutically acceptable solvates include, but are not limited to, compounds prepared using water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.
In the case of solid formulations, it is understood that the inventive compounds can exist in different forms, such as stable and metastable crystalline forms and isotropic and amorphous forms, all of which are intended to be within the scope of the present invention.
A xe2x80x9cpharmaceutically acceptable saltxe2x80x9d is intended to mean those salts that retain the biological effectiveness and properties of the free acids and bases and that are not biologically or otherwise undesirable.
Examples of pharmaceutically acceptable salts include, but are not limited to, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.
If the inventive compound is a base, the desired salt can be prepared by any suitable method known in the art, including treatment of the free base with an inorganic acid, such as hydrochloric acid; hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid; and the like, or with an organic acid, such as acetic acid; maleic acid; succinic acid; mandelic acid; fumaric acid; malonic acid; pyruvic acid; oxalic acid; glycolic acid; salicylic acid; pyranosidyl acids such as glucuronic acid and galacturonic acid; alpha-hydroxy acids such as citric acid and tartaric acid; amino acids such as aspartic acid and glutamic acid; aromatic acids such as benzoic acid and cinnamic acid; sulfonic acids such a p-toluenesulfonic acid or ethanesulfonic acid; or the like.
If the inventive compound is an acid, the desired salt can be prepared by any suitable method known in the art, including treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary, or tertiary), an alkali metal or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine; ammonia; primary, secondary, and tertiary amines; and cyclic amines such as piperidine, morpholine, and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum, and lithium.
All inventive compounds that contain at least one chiral center can exist as single stereoisomers, racemates, and/or mixtures of enantiomers and/or diastereomers. All such single stereoisomers, racemates, and mixtures thereof are intended to be within the scope of the present invention. Preferably, the compounds of the present invention are used in a form that contains at least 90% of a single isomer (80% enantiomeric or diastereomeric excess), more preferably at least 95% (90% e.e. or d.e.), even more preferably at least 97.5% (95% e.e. or d.e.), and most preferably at least 99% (98% e.e. or d.e.). Compounds identified herein as single stereoisomers are meant to describe compounds used in a form that contains at least 90% of a single isomer.